ANATOMY OF THE SKIN
Maged N. Kamel, M.D.
ANATOMY OF THE SKIN
Maged N. Kamel, M.D.
Sensory Apparatus of the Skin
The skin is innervated with around one million afferent nerve fibers. Most
terminate in the face and extremities; relatively few supply the back. The
cutaneous nerves contain axons with cell bodies in the dorsal root ganglia.
Their diameters range from 0.2-20 µm. The main nerve trunks entering the
subdermal fatty tissue each divide into smaller bundles. Groups of myelinated
fibers fan out in a horizontal plane to form a branching network from which
fibers ascend, usually accompanying blood vessels, to form a mesh of interlacing
nerves in the superficial dermis. Throughout their course, the axons are
enveloped in Schwann cells and as they run peripherally, an increasing number
lack myelin sheaths. Most end in the dermis; some penetrate the basement
membrane, but do not travel far into the epidermis.
Sensory endings are of two main kinds: corpuscular, which embrace
non-nervous elements, and 'free', which do not. Corpuscular endings can, in
turn, be subdivided into encapsulated receptors, of which a range occurs in the
dermis, and non-encapsulated, exemplified by Merkel's 'touch spot' which is
epidermal.
Each Merkel's touch spot is composed of a battery of
Merkel cells borne on branches of a myelinated axon. A Merkel cell has a
lobulated nucleus and characteristic granules; it is embedded in the basal layer
of epidermal cells, with which it has desmosomal connections; it contains
intermediate filaments composed of low molecular weight keratin rather than
neurofilament protein.
The Pacinian corpuscle is one of the
encapsulated receptors. It is an ovoid structure about 1mm in length, which is
lamellated in cross-section like an onion, and is innervated by a myelinated
sensory axon which loses its sheath as it traverses the core. The Golgi-Mazzoni
corpuscle found in the subcutaneous tissue of the human finger is similarly
laminate but of much simpler organization. These last two lamellated end organs
are movement and vibration detectors.
The Krause end bulb is an encapsulated swelling on myelinated fibers
situated in the superficial layers of the dermis. Meissner corpuscles are
characteristics of the papillary ridges of glabrous (hairless skin) skin; they
are touch receptors; they have a thick lamellated capsule, 20-40 µm in diameter
and up to 150 µm long. Ruffini endings in the human digits have several expanded
endings branching from a single myelinated afferent fibre; the endings are
directly related to collagen fibrils; they are stretch receptors.
'Free nerve endings', which appear to be derived from non-myelinated
fibers occur in the superficial dermis and in the overlying epidermis; they are
receptors for pain, touch, pressure and temperature. Hair follicles have fine
nerve filaments running parallel to and encircling the follicles; each group of
axons is surrounded by Schwann cells; they mediate touch sensation.
The brain receives two types of sensations: (1) superficial
sensations, including pain, temperature and crude touch, and (2) deep
sensations, including sense of position, sense of movement, vibration sense,
muscle sense and fine touch. Some superficial and deep sensations must reach the
cortex to be felt. These are: (1) tactile localization, tactile discrimination
and stereognosis, (2) mid-zones of temperarure (between very hot and very cold
values), and (3) sense of position and movement.
Pathway of pain, temperature and crude touch sensations: (1)
The first order neuron is present in the posterior root ganglion. Its dendrite
passes to the periphery to act as a pain receptor, while its axon passes towards
the spinal cord. In the spinal cord, it ascends for one or few segments at the
tip of the posterior horn forming the Lissauer's tract, and then ends around the
cells of the substantia gelatinosa of Rolandi which are present at the tip of
the posterior horn of the grey matter. (2) The second order neuron is present in
the substantia gelatinosa of Rolandi. Its axon crosses to the opposite side in
the anterior commissure near the central canal, then ascends in the lateral
spinothalamic tract (ventral spinothalamic tract, in case of crude touch) to
terminate in the thalamus. (3) The third order neuron is present in the
thalamus. Its axon travels in the posterior limb of the internal capsule behind
the pyramidal fibers and terminates in the sensory area of the cerebral cortex
(areas 1, 2, and 3).
Pathway of deep sensations and
fine touch: (1) The first order neuron is also present in the posterior root
ganglion. Its dendrite passes to the periphery, while its axon enters the spinal
cord and ascends directly (without relay) in the posterior column of the spinal
cord, forming the Gracile and Cuneate tracts. The two tracts end in the medulla
around the Gracile and Cuneate nuclei. (2) The second order neuron is present in
the Gracil and Cuneate nuclei of the medulla. Its axon crosses to the opposite
side then ascends in the brain stem (forming the medial lemniscus) to reach the
thalamus where it terminates. (3) The third order neuron is present in the
thalamus. Its axon passes upwards in the internal capsule to end in the sensory
area of the cerebral cortex.
Physiology of Sensory Receptors
Adaptation: When a maintained stimulus of constant strength is applied
to a receptor, the frequency of the action potentials in its sensory nerve
declines over time. There are two types of receptors: (1) tonic slowly-adapting
receptors: as the nociceptors (pain receptors) which continue to transmit
impulses to the brain as long as the stimulus is applied, thus keeping the CNS
continuously informed about the state of the body; and (2) phasic
rapidly-adapting receptors: as Pacinian corpuscles--these receptors adapt
rapidly and cannot be used to transmit a continuous signal to the CNS -they are
stimulated only when the stimulus strength is changed.
Touch sensation is provoked by a harmless stimulus to the skin
allowing us to distinguish between hard and soft objects; touch receptors belong
to the class of mechanoreceptors and many of them can be found around hair
follicles, so removal of hair decreases touch sensitivity; the tips of the
fingers and lips are rich in touch receptors.
Tickle and itch: These sensations are experienced when mild
stimulation of the pain nerve endings occurs; there are also specific free nerve
endings for itch sensation; tickle and itch sensations are transmitted by group
C unmyelinated nerve fibers; histamine produces itch while pain signals suppress
it; tickle is itch produced by light external moving stimuli and is a
pleasurable sensation; itch is an annoying sensation while pain is unpleasant;
itch sensation excites the scratch reflex.
Endorphins and enkephalins are important opioid neurotransmitters in
the CNS that mediate the sensation of itch. Although morphine alleviates pain,
it aggravates itch, as itch and pain share common neurological pathways. The
central elicitation of itch by morphine results from binding to opioid receptors
and this binding may mimic normal physiological binding of endorphins and
enkephakins at these receptor sites. Naloxone, an opioid antagonist, has been
found to reduce histamine-provoked itch.
The heparin-containing tissue cells called mast cells have a high
histamine content in their granules. They also contain serotonin. Mast cells are
particularly numerous in the skin (about 7,000 mast cells per cubic millimeter
in normal skin in the subpapillary dermis). Mast cells play an important role in
type I immediate hypersensitivity reation (IgE-mediated anaphylactic
reaction). n ,
Temperature sensation: Receptors for warmth and
cold are specialized free nerve endings; a rise in skin temperature above body
temperature causes a sensation of warmth, while a fall in skin temperature below
body temperature is experienced as cold sensation; pain is felt if skin
temperature increases above 45 °C or decreases below 10 °C; the mucous membrane
of the mouth is less sensitive than the skin, thus tea can be drunk at a
temperature which is painful to fingers.
Paradoxical cold: Cold receptors are stimulated by intrinsic heat
(e.g., shivering that occurs with fever).
Pain is evoked by non-specific stimuli (chemical, mechanical,
thermal, or electrical) of an intensity which can produce tissue damage. Pain is
a high threshold sensation. The nociceptors (pain receptors) are free nerve
endings. Cutaneous pain may be sharp and localized, or dull and diffuse. A
painful stimulus causes at first sharp pain, followed by dull aching pain.
Reflex withdrawal movements also occur, with an increase in heart rate and blood
pressure. Fast sharp (pricking) pain is mediated by nociceptors innervated by
group A delta thick myelinated nerve fibers which transmit pain impulses at a
velocity of 20 meter/second. Slow chronic (dull-aching or burning) pain is
mediated by nociceptors innervated by group C thin unmyelinated nerve fibers
that conduct pain at a low velocity of 1 meter/second.
Algogenic substances: These are pain-producing substances either
exogenous (as acids and alkalies), or endogenous (as prostaglandins, bradykinin,
ATP, 5-HT [serotonin], and histamine).
Types
of Hyperalgesia: (1) Primary hyperalgesia: Hypersensitivity of pain receptors
(lowered pain threshold, so that touch can produce pain). It is due to release
of algogenic substances (as histamine and prostaglandins) in an inflamed area of
the skin (e.g., sunburn). (2) Secondary hyperalgesia: It is not due to a skin
lesion. The cause is a CNS lesion (e.g., thalamic syndrome [see: Cutaneous
Sensory System: Connection to CNS] and herpes zoster) with facilitation of
sensory transmission. The pain threshold in secondary hyperalgesia is normal or
elevated, but the pain produced is unpleasant, prolonged and severe.
Circulation through the skin serves two functions: (1) nutrition of the skin
tissue, and (2) regulation of body temperature by conducting heat from the
internal structures of the body to the skin, where it is lost by exchange with
the external environment (by convection, conduction and radiation). (See Also:
Sweat Glands.)
The cutaneous circulatory apparatus is well-suited to
its functions. It comprises two types of vessels: (1) the usual nutritive
vessels (arteries, capillaries and veins), and (2) vascular structures concerned
with heat regulation. The latter include an extensive subcutaneous venous plexus
which can hold large quantities of blood (to heat the surface of the skin), and
arteriovenous anastomoses which are large direct vascular communications between
arterial and venous plexuses. Arteriovenous anastomoses are only present in some
skin areas which are often exposed to maximal cooling, as the volar surfaces of
hands and feet, the lips, the nose and the ear.
The specialized vascular structures just mentioned, bear strong
muscular coats innervated by sympathetic adrenergic vasoconstrictor nerve
fibers. When constricted, blood flow into the subcutaneous venous plexus is
reduced to almost nothing (minimal heat loss); while, when dilated, extremely
rapid flow of warm blood into the venous plexus is allowed (maximal heat
loss).
The blood flow required for the nutrition of the skin
is very small (about 40ml/min). Yet, at ordinary skin temperature, the amount of
blood flowing through the skin is 10 times (=0.25L/m2 =400ml/min in a normal
adult) more than what is needed for the nutrition of the tissues.
The rate of cutaneous blood flow required to regulate body
temperature varies in response to changes in the metabolic activity of the body
and/or the temperature of the surroundings. Exposure to extreme cold reduces the
rate of blood flow to very low values, so that the nutritive function may
sometimes suffer. On the other hand, heating the skin until maximal
vasodilatation occurs (as in hot climate), increases the cutaneous blood flow 7
times the normal value (2.8L/min.). This diminishes the peripheral resistance
and increases the cardiac output, which may lead to the decompensation of the
heart in borderline-heart-failure subjects exposed to hot weather.
Located in the anterior hypothalamus is a small center that controls
body temperature. Heating this area causes vasodilatation of all the skin
vessels of the body and sweating. On the contrary, cooling this center causes
vasoconstriction of skin vessels and stoppage of sweat secretion. The
hypothalamus exerts its controlling effect on the skin vessels through
sympathetic nerves. There are also vasoconstrictor reflex centers in the spinal
cord.
Sympathetic noradrenergic vasoconstrictor fibers
supply the vessels of the skin throughout the body. This constrictor system is
extremely powerful in the feet, hands, lips, nose and ears (areas where large
numbers of arteriovenous anastomoses are found). At normal body temperature, the
sympathetic vasoconstrictor nerves keep these anastomoses closed. However, when
the body becomes overheated, the sympathetic discharge is greatly reduced so
that the anastomoses dilate allowing large quantities of warm blood to flow into
the subcutaneous venous plexus, thereby promoting heat loss from the body.
Active vasodilatation of the blood vessels of the skin of forearms
and trunk may be due to the discharge of sympathetic cholinergic vasodilator
fibers supplying these areas. The increased activity of sweat glands in hot
weather may also contribute to the vasodilatation by releasing kallikrein, an
enzyme which splits the polypeptide bradykinin from a globulin present in the
interstitial spaces. Bradykinin is a powerful vasodilator.
In cold weather, when the temperature reaches 15 °C, we get maximal
vasoconstriction of skin blood vessels. However, in a normal subject, if the
skin temperature is lowered below 15 °C, the cutaneous vessels begin to dilate.
This dilatation is attributed to the direct local effect of cold causing
paralysis of the contractile musculosa of skin blood vessels and blocking nerve
impulses to the vessels. Maximal vasodilatation occurs at 0 °C, increasing the
blood flow through the skin which prevents freezing of the exposed areas of the
body.
The cutaneous circulation also serves as a blood
reservoir. Under conditions of circulatory stress, e.g., exercise and
hemorrhage, sympathetic stimulation of subcutaneous venous plexus forces a large
volume of blood (5-10% of the blood volume) into the general circulation.
Reactive hyperaemia occurs if one, for example, sits on one portion
of his skin for 30 minutes or more then removes the pressure. In such
conditions, the individual will notice intense redness of the skin at the site
of previous pressure, which resulted from accumulation of vasodilator
metabolites at that site (due to decreased availability of nutrients to the
tissues during compression).
The triple response: A firm stroke applied to the skin results
in three local reactions collectively known as the triple response: (a) at first
blanching of the skin occurs for a very brief moment (due to pressure exerted by
the stroke), followed by a red line due to capillary dilatation (caused by
histamine and other mediators of vasodilatation released from damaged tissues);
(b) a red flare follows the red line by 20-40 seconds and is due to arteriolar
dilatation through a local axon reflex (the axon reflex is caused by stimulation
of the pain nerve fibers with impulses passing up these fibers and down to their
endings where vasodilator algogenic--i.e, pain-inducing--substances are
released); (c) finally, a wheal may appear after 1 minute, reaching full
development within 5 minutes (the wheal is best seen in people with
hypersensitive skin; it is due to release of histamine which causes arteriolar
dilatation and venular constriction, raising the capillary blood pressure with
transudation of fluid into the tissues).
The epidermis is a multilayered structure (stratified epithelium) which
renews itself continuously by cell division in its deepest layer, the basal
layer. The principal cell type, the epidermal cell, is most commonly referred to
as a keratinocyte. The cells produced by cell division in the basal layer
constitute the prickle cell layer and as they ascend towards the surface they
undergo a process known as keratinization which involves the synthesis of the
fibrous protein keratin. The total epidermal renewal time is 52-75 days. The
cells on the surface of the skin, forming the horny layer (stratum corneum), are
fully keratinized dead cells which are gradually abraded by day to day wear and
tear from the environment.
The basal layer is composed of columnar cells which are anchored to a
basement membrane--this lies between the epidermis and dermis. The basement
membrane is a multilayered structure from which anchoring fibrils extend into
the superficial dermis. Interspersed amongst the basal cells are melanocytes,
large dendritic cells responsible for melanin pigment production.
The prickle cell layer acquires its name from the spiky appearance
produced by intercellular bridges (desmosomes) which connect adjacent cells.
Scattered throughout the prickle cell layer are numbers of dendritic cells
called Langerhans cells. Like macrophages, Langerhans cells originate in the
bone marrow and have an antigen-presenting capacity.
Above the prickle cell layer is the granular layer which is composed
of rather flattened cells containing numerous darkly-staining particles known as
keratohyaline granules. Also present in the cytoplasm of cells in the granular
layer are organelles known as lamellar granules (Odland bodies). Lamellar
granules contain lipids and enzymes, and they discharge their contents into the
intercellular spaces between the cells of the granular layer and stratum
corneum, providing something akin to 'mortar' between the cellular 'bricks.' In
the granular layer the cell membranes become thickened as a result of deposition
of dense material on their inner surfaces.
The cells of the stratum corneum are flattened keratinized cells
which are devoid of nuclei and cytoplasmic organelles. These cellular components
degenerate in the upper granular layer. Adjacent cells overlap at their margins
and this locking together of cells, together with intercellular lipid, forms a
very effective barrier. The stratum corneum varies in thickness depending on the
region of the body, being thickest over the palms of the hands and soles of the
feet.
The rate of cell production in the germinative
compartment of the epidermis must be balanced by the rate of cell loss at the
surface of the stratum corneum. The control mechanism of epidermopoiesis
consists of a balance of stimulatory and inhibitory signals. Wound healing
provides a model to examine the changes in growth control that occur in
establishing a new epidermis. Wounding of the skin is followed by a wave of
epidermal mitotic activity, which represents the effects of diffusible factors
spreading from the wound into the surrounding tissue. These factors include
cytokines and growth factors. There production is not limited to immune cells as
they are produced by keratinocytes in vitro and can be found in physiological
amounts in normal human skin.
Regulation of Epidermopoiesis: Stimulatory Factors
The growth factors which stimulate the epidermal cells include: epidermal
growth factor (EGF), transforming-growth-factor-alpha (TGFalpha), interleukins
(IL) and other immunological cytokines, and basic fibroblast growth factor
(bFGF).
EGF binds to specific cell-surface receptors (EGFR, a
trans-membrane glycoprotein receptor) present in the basal layer of the human
epidermis. Following binding of EGF to EGFR, the receptor is internalized and
carries EGF into an intracellular cycle within the cytoplasm and the nucleus to
mediate all its effects. EGF has been shown to increase the growth and
persistence of epidermal keratinocytes and to promote wound healing in vitro.
EGF transcripts are not found in the epidermis, but in salivary glands and
intestinal tract.
TGFalpha was the first growth factor known to be
produced by keratinocytes. Its mRNA predominates in the basal compartment of the
epidermis. TGFalpha is related to EGF. It binds to and activates the EGF
receptor. It stimulates keratinocyte growth.
The normal epidermis also contains large amounts of Interleukin-1.
There are two forms, alpha and beta, and unlike macrophages, the epidermis
largely produces IL-1alpha. IL-1 has been shown to be mitogenic for
keratinocytes (other effects include: fibroblast proliferation and synthesis of
collagenase, stimulation of IL-2 production, stimulation of B-cell function, and
fever induction). IL-1 releases IL-6 from keratinocytes. IL-6 appears to
stimulate growth of keratinocytes and can be detected in epidermal cells.
Keratinocytes also synthesize IL-3, IL-4, IL-8 (neutrophil activating protein),
and granulocyte-macrophage colony stimulating factor.
Thus the epidermal keratinocytes can, under activation conditions,
secrete a large number of cytokines, which can modulate lymphocyte activation
and granulocyte function. These factors do not work in isolation but have
complex interactions, and may be synergistic or antagonistic. The factors
controlling synthesis and secretion of these factors may be important in the
pathogenesis of skin disease as well as epidermal growth control.
The regulation of the effects of growth factors includes the control
of expression of the specific growth-factor receptors. The epidermal cell cycle
is also controlled by the intracellular concentrations of the cyclic
nucleotides: cAMP and cGMP. These are small molecules which are formed and
broken down intracellularly as a response to external signals acting on the cell
membrane. Cyclic AMP is believed to be the intracellular agent or '2nd
messenger' of those hormones, i.e. catecholamines and polypeptides, which do not
themselves penetrate the surface of cells. Cyclic AMP inhibits epidermal cell
division while cGMP stimulates it. Epidermal mitosis exhibits a circadian
rhythm, which is inversely related to blood adrenaline levels.
Steroid hormones like testosterone enter the target cells. Epidermal
keratinocytes contain 5 alpha-reductase enzyme and they can convert testosterone
to 5 alpha-dihydrotestosterone (DHT). DHT binds to specific cytosol receptors
which then translocate to the nucleus, thereafter, altering protein synthesis
via messenger RNA. Androgens and vitamin A stimulate epidermal mitosis, while
glucocorticoid hormones inhibit it.
Prostaglandins, which are metabolic products of arachidonic acid, can
affect nucleotide metabolism. Prostaglandins of the D and E series can increase
cAMP, although not all such components are present in the epidermis. The main
prostaglandin formed in the epidermis is PGE2. On the other hand, lipoxygenase
products of arachidonic acid metabolism namely HETE
(12-Hydroxy-Eicosa-Tetra-Enoic acid) and the leucotrienes are capable of
inducing epidermal cell proliferation in vitro.
Polyamines, including spermidine, putrescein and spermine, stimulate
mitosis. Ornithine decarboxylase is a particularly important enzyme for the
generation of this group of substances.
Regulation of Epidermopoiesis: Inhibitory Factors
Growth inhibitors for keratinocytes include chalones,
transforming-growth-factor-beta (TGFbeta), alpha and gamma interferons
(IFN-gamma), and tumour necrosis factor (TNF).
Chalones are polypeptides produced by suprabasal cells which slow
basal mitosis. TGFbeta stimulates fibroblast growth and increases fibrosis but
inhibits the growth of keratinocytes. Thus although it may have an inhibitory
effect on epidermal growth the effect on wound healing is complex, because of
mesenchymal effects (on fibroblasts) and it has been reported to stimulate wound
healing.
Alpha and gamma interferons have cytostatic effects on
keratinocytes both in vivo following systemic administration and in vitro.
Following stimulation with IFN-gamma, keratinocytes express class II antigens,
predominantly HLA-DR. High doses of Interferon-gamma are cytotoxic.
Thirty percent of administered TNF localizes in epidermis suggesting
the presence of many TNF-binding sites. Keratinocytes also secrete TNF. TNF can
cause release of IL-1. It stimulates fibroblast proliferation and cytokine
production. TNF has also been shown to be reversibly cytostatic to
keratinocytes.
The skin is structured to prevent loss of essential body fluids, and to
protect the body against the entry of toxic environmental chemicals. In the
absence of a stratum corneum we would all lose significant amounts of water to
the environment, and rapidly become dehydrated. The stratum corneum with its
overlapping cells and intercellular lipid, makes diffusion of water into the
environment very difficult.
The skin is also part of the innate immunity (natural resistance) of
the body against invasion by micro-organisms. The dryness and constant
desquamation of the skin, the normal flora of the skin, the fatty acids of sebum
and lactic acid of sweat, all represent natural defense mechanisms against
invasion by micro-organisms. Langerhans cells present in the epidermis have an
antigen-presenting capacity and might play an important role in delayed
hypersensitivity reactions. They also play a role in immunosurveillance against
viral infections. Langerhans cells interact with neighboring keratinocytes,
which secrete a number of immunoregulating cytokines, and epidermotropic T-cells
forming the skin immune system: SALT (skin associated lymphoid tissue).
Melanin pigment of the skin protects the nuclear structures against
damage from ultraviolet radiation.
The skin is also a huge sensory receptor for heat, cold, pain, touch,
and tickle. Parts of the skin are considered as erogenous zones. The skin has
great psychological importance at all ages. It is an organ of emotional
expression and a site for the discharge of anxiety. Caressing favors emotional
development, learning and growth of newborn infants.
The skin is a vital part of the body's temperature regulation system,
protecting us against hypothermia and hyperthermia, both of them may be fatal
(specialized vascular structures of the dermis/insulation by fat in subcutaneous
tissue/evaporation of sweat).
The skin plays an important role in calcium homeostasis by
contributing to the body's supply of vitamin D. Vitamin D3 (cholecalciferol) is
produced in the skin by the action of ultraviolet light on dehydrocholesterol.
It is then hydroxylated in the liver and kidneys (needs parathyroid hormone to
activate alpha-hydroxylase) to 1,25 dihydroxycholecalciferol, the active form of
vitamin D. This anti-rachitic vitamin acts on the intestine increasing calcium
absorption (through stimulation of synthesis of calcium-binding proteins in the
mucosal cells of the intestine), as well as on the kidneys promoting calcium
reabsorption.
Fingerprints, the characteristic elevated ridge
patterns on the finger tips of humans, are unique to each individual. The
fingers and toes, the palms of the hands and soles of the feet, are covered with
a system of ridges which form certain patterns. The term dermatoglyphics is
applied to both the configurations of the ridges, and also to the study of
fingerprints. The medicolegal importance of the ridge patterns of fingerprints,
characteristic dermatoglyphic abnormalities frequently accompany many
chromosomal aberrations.
Hair performs no vital function in humans, whose body could be perpetually
depilated without any physiological disadvantages. At the same time the
psychological functions are inestimable: scalp hair is a major social and sexual
display feature of the human body.
Hairs grow out of tubular invaginations of the epidermis known as
follicles, and a hair follicle and its associated sebaceous glands are referred
to as a pilosebaceous unit. Hair follicles extend into the dermis at an angle. A
small bundle of smooth muscle fibers, the arrector pili muscle, extends from
just beneath the epidermis and is attached to the side of the follicle at an
angle. Arrector pili muscles are supplied by adrenergic nerves, and are
responsible for the erection of hair during cold or emotional stress ('goose
flesh'). The sebaceous gland is attached to the follicle just above the point of
attachment of the arrector pili.
At the lower end of the follicle is the hair bulb, part of which, the
hair matrix, is a zone of rapidly dividing cells which is responsible for the
formation of the hair shaft. Hair pigment is produced by melanocytes in the hair
bulb. Cells produced in the hair bulb become densely packed, elongated and
arranged parallel to the long axis of the hair shaft. They gradually become
keratinized as they ascend in the hair follicle.
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The main part of each hair fibre is the cortex, which is composed of keratinized spindle-shaped cells. Terminal hair (as that of scalp) have a central core known as the medulla consisting of specialized cells which contain air spaces (see: Types of Hair). Covering the cortex is the cuticle, a thin layer of cells which overlap like the tiles on a roof, with the free margins of the cells pointing towards the tip of the hair. |
The cross-sectional shape of hair varies with body site and with race.
African hair is distinctly oval in cross-section, and pubic, beard and eyelash
hairs are oval in all racial types. The form of scalp hair also differs among
human races (e.g., the peppercorn pattern in black Africans).
The average rate of growth of human scalp hair is 0.37mm per day. In
women scalp hair grows faster and body hair grows more slowly than in men. The
rate of growth of body hair is undoubtedly increased by androgens, since it can
be reduced by treatment with antiandrogenic steroids.
Hair: Types and Growth Cycle
The first hair to be produced by the fetal follicles, so called lanugo, is
fine, soft, unmedullated, and usually unpigmented. Lanugo is normally shed in
utero in the seventh or eighth month of gestation.
Postnatal hair can be divided into vellus, which is soft
unmedullated, usually unpigmented, and seldom more than 2cm long, and terminal
hair, which is longer, coarser, and often medullated and pigmented. There is,
however, a range of intermediate types.
The type of hair produced by any particular follicle can change. The
most striking example is the replacement of vellus by terminal hair at puberty
which starts in the pubic regions. This leads us to the definition of
androgen-dependent hair. It is obvious from the events of puberty that pubic,
axillary, facial, and body hair are hormone-dependent. So, paradoxically, is
pattern baldness (male), in which terminal hair is replaced by fine, short hair
resembling vellus. The growth of male beard depends on testicular hormones. The
action of testosterone in general involves its reduction to 5
alpha-dihydrotestosterone and binding to an intracellular receptor.
The most important feature of hair follicles is that their activity
is intermittent (cyclical). As the hair reaches a definitive length, it is shed
to be replaced by a new hair. Thus a hair follicle will pass into three stages:
an active (anagen) stage, a resting (catagen) stage, and a telogen stage where
the hair stops growing to be finally shed. In human scalp hair, the anagen stage
takes about three years, the catagen stage takes three weeks, and the telogen
phase takes three months. The hair cycle occurs in different hair follicles
asynchronously, i.e., at a given time, each individual hair follicle is at a
different stage of the hair cycle.
Electron microscopical examination of cells from all tissues reveals that
they contain a complex, heterogenous, intracytoplasmic system of filaments. The
components of this system include actin, myosin, and tubulin, whose diameters
average approximately 60A°, 150A°, and 250A°, respectively. In addition, other
intracytoplasmic filaments were noted, and since the diameter of these latter
structures was found to be between 70 and 100A°, they were called intermediate
filaments.
Intermediate filaments form a major part of the
cytoskeleton of most cells and fulfill a variety of roles related to cell shape,
spatial organization, and perhaps informational transfer. The nucleus contains
structures related to these intermediate filaments and many intracellular
components including polyribosomes, mitochondria, nucleic acids, enzymes, and
cyclic nucleotides are attached to the cytoskeleton.
Based on their biochemical, biophysical, and antigenic properties, a
number of classes of intermediate filaments can be recognized in different cell
types: desmin (skeletin) in muscle cells, glial fibrillary acidic filaments in
glial cells, neurofilaments in neurons, vimentin in mesenchymal cells, and
keratin in epithelial cells. In cultured epidermal cells, keratins account for
up to 30% of the cellular protein, while in stratum corneum, keratin accounts
for up to 85% of the cellular protein.
At least 19 keratin proteins can be identified ranging in molecular
weight from approximately 40,000 to 68,000 micrograms. Moll and his coworkers
published their human keratin catalogue in 1982. According to this catalogue,
there are two keratin subfamilies. The molecular weight of the members of one
(the basic subfamily) is relatively larger than that of the members of the other
(the acidic subfamily). Each of the keratins is the product of a unique gene
and, in essentially all situations, the keratins are expressed as pairs
containing one member of each subfamily. The two members of each pair are in the
same size rank order within their respective family, e.g., the largest acidic
keratin is expressed with the largest basic.
The type of keratin differs in different tissues, i.e, there are
different types of keratin for keratinized epidermis, hyperproliferative
epidermis of palms and soles, corneal epithelium, stratified epithelium of the
esophagus and cervix, and simple epithelium of the epidermal glands. As
mentioned before, keratin is the main structural protein of the epidermis.
The keratinocytes in the basal layer and prickle cell layer
synthesize keratin filaments (tonofilaments) which aggregate into bundles
(tonofibrils). Eventually, in the cells of the stratum corneum, these bundles of
keratin filaments form a complex intracellular network embedded in an amorphous
protein matrix. The matrix is derived from the keratohyaline granules of the
granular layer. Epidermal keratinization results in the production of a barrier
which is relatively impermeable to substances passing in or out of the body.
The nail acts as a protective covering to the end of the digit and assists in
grasping small objects. The nail has also a cosmetic function. The major part of
this appendage is the hard nail plate, which arises from the matrix (see below).
The nail plate is roughly rectangular and flat in shape but shows considerable
variation in different persons. The pink color of the nail bed results from its
extensive vascular network and can be seen because of the transparency of the
plate.
Usually in the thumbs, uncommonly in other fingers and
in the large toenails, a whitish crescent-shaped lunula is seen projecting from
under the proximal nail folds. The lunula is the most distal portion of the
matrix and determines the shape of the free edge of the nail plate. Its color is
due in part to the effect of light scattered by the nucleated cells of the
matrix and in part to the thick layer of epithelial cells making up the
matrix.
As the nail plate emerges from the matrix, its lateral
and proximal borders are enveloped by folds of the skin termed the lateral and
proximal nail folds. The skin underlying the free end of the nail is referred to
as the hyponychium and is contiguous with the skin on the tip of the finger.
The nail plate is formed by a process which involves flattening of
the basal cells of the matrix, fragmentation of the nuclei, and condensation of
cytoplasm to form horny flat cells which are strongly adherent to one another.
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Fingernails grow faster than toenails. Nails of individual fingers of the
same hand grow at different rates. There are also familial tendencies favouring
similar growth rates among persons and it has been noted that nail growth is
increased during summer and diminished in cold climates.
Many systemic disorders may produce a decrease in the rate of nail
growth or thinning and grooving of the plate. This phenomenon is best
appreciated weeks after the event has occured. Acute viral infectious diseases
as mumps and measles, starvation, and some types of anaemia are among the
causes. Increase in the growth rate can be seen during pregnancy, nail biting,
trauma and during regrowth after avulsion.
Melanocytes and Skin Color
The melanin pigmentary system is composed of functional units called
epidermal melanin units. Each unit consists of a melanocyte that supplies
melanin pigment to a group of keratinocytes (about 36). Pigmentation is
determined primarily by the amount of melanin transferred to the
keratinocytes.
The melanocyte is a dendritic cell present in the
basal layer of the epidermis with no desmosomes (intercellular bridges) or
tonofilaments. In H & E-stained sections, it has a small dark nucleus and a
clear cytoplasm. It can be stained black with Fontana Masson (Silver) stain as
it contains melanin, and more specifically with DOPA reaction as it has the
ability to form melanin (tyrosinase-containing cell).
Melanocytes arise from the neural crest as melanoblasts and migrate
to the dermis, hair follicles, leptomeninges, uveal tract and retina. By the 8th
week of intrauterine life, they start to migrate from the dermis to the
epidermis. Although full melanocyte migration is normally completed prior to
birth, residual dermal melanocytes are sometimes left (clinically appearing as
mongoloid spots in the sacral area of oriental and black infants).
Melanosomes are membrane-bound organelles located in the cytoplasm of
melanocytes and bearing tyrosinase enzyme. They are responsible for melanin
synthesis and pigment transfer from the melanocyte to the surrounding
keratinocytes. During their passage from the perinuclear area of the melanocyte
to the dendrites, the melanosomes show four stages of development: I and II
(with no melanin deposition), III (with high levels of tyrosinase activity and
is partially obscured by melanin deposition), and IV (with low levels of
tyrosinase activity and is completely obscured by melanin deposition). Pigment
transfer occurs by keratinocyte phagocytosis of melanosome-containing dendritic
tips. As squamous cells differentiate, the melanosomes within them are degraded
by lysosomal enzymes.
The differences in racial
pigmentation are not due to differences in the number of melanocytes, but rather
to differences in melanocyte activity. In black skin, there is greater
production of melanosomes, higher degree of melanization of melanosomes, and
larger unaggregated melanosomes showing slow rate of degradation.
Melanin: Types, Synthesis and Hormonal Regulation
Melanin is a brown-black, light-absorbing pigment, protecting the skin
against ultraviolet rays. Two major forms of melanin exist in humans: (1)
Eumelanin, a brown to black pigment synthesized from Indole 5,6-quinone and
found within the ellipsoid melanosomes; and (2) Phaeomelanin, a yellow-red
pigment found within the spherical melanosomes.
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Tyrosinase is synthesized by the ribosomes of the rough endoplasmic reticulum (rER) and transported through the smooth endoplasmic reticulum (sER) to the Golgi apparatus. It is then released within membrane-bound vesicles. Meanwhile, structural melanosomal proteins are also synthesized on the rER and are then incorporated into vesicles at the sER. Fusion of the two types of vesicles (tyrosinase and structural melanosomal proteins) results in the formation of a melanosome. As the melanosome matures and more melanin is deposited on its lamellar matrix, it passes into the dendrite of the melanocyte. |
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There are receptors on the surface of melanocytes for melanocyte-stimulating
hormone (MSH). MSH, ACTH (similar to MSH in the arrangement of first 13 amino
acids), estrogen and progesterone, all stimulate pigmentation through increasing
cAMP and tyrosinase activity, resulting in increased melanin formation and
transfer.
Sebaceous glands are found on all areas of the skin with the exception of the
palms, soles, and dorsa of the feet. They are holocrine glands, i.e., their
secretion is formed by complete destruction of the cells.
Most sebaceous glands have their ducts opening into hair follicles
(pilosebaceous apparatus). Free sebaceous glands (not associated with hair
follicles) open directly to the surface of the skin, e.g., Meibomian glands of
the eyelids, Tyson's glands of the prepuce, and free glands in the female
genitalia and in the areola of nipples.
The production of sebum is under hormonal control and sebaceous
secretion is a continuous process. Sebaceous gland development is an early event
in puberty, and the prime hormonal stimulus for this glandular development is
androgen. Although the sebaceous glands are very small throughout the
prepubertal period, they are large at the time of birth, probably as a result of
androgen stimulation in utero, and acne may be seen in the neonatal period. It
should be noted that: (1) sebum production is low in children; (2) in adults,
sebum production is higher in men than in women; (3) in men, sebum production
falls only slightly with advancing age, whereas in women it decreases
significantly after the age of 50. Orchidectomy causes a marked decrease in
sebum production. Therefore, it can be assumed that testicular androgen
maintains sebum production at high levels in men. The role of adrenal androgens
is also important, specially in women where they play a contributory role in
sebum production together with the ovaries.
Estrogens have a profound effect on sebaceous gland function which is
opposite of that of androgens. In both sexes, estrogen administration decreases
the size of the sebaceous glands and the production of sebum.
The sebum is composed of triglycerides and free fatty acids, wax
esters, squalene, and cholesterol. The sebum controls moisture loss from the
epidermis. The water-holding power of cornified epithelium depends on the
presence of lipids. The sebum also protects against fungal and bacterial
infections of the skin due to its contents of free fatty acids. Ringworm of
scalp becomes rare after puberty.
Generalized sweating is the normal response to exercise or thermal stress by
which human beings control their body temperature through evaporative heat loss.
Failure of this mechanism can cause hyperthermia and death. (See Also: Cutaneous
Vascular System.)
Humans have several million eccrine sweat glands
distributed over nearly the entire body surface (except labia minora and glans
penis). The total mass of eccrine sweat glands roughly equals that of one
kidney, i.e., 100g. A person can perspire as much as several litres per hour and
10 litres per day, which is far greater than the secretory rates of other
exocrine glands such as the salivary and lacrimal glands and the pancreas.
Each eccrine sweat gland consists of a secretory coil deep in the
dermis, and a duct which conveys the secreted sweat to the surface. The
secretory activity of the human eccrine sweat glands consists of two major
functions: (1) secretion of an ultrafiltrate of a plasmalike precursor fluid by
the secretory coil in response to acetylcholine released from the sympathetic
nerve endings, and (2) reabsorption of sodium in excess of water by the duct,
therby producing a hypotonic skin surface sweat. Under extreme conditions where
the amount of perspiration reaches several litres a day, the ductal reabsorptive
function assumes a vital role in maintaining homeostasis of the entire body.
In addition to the secretion of water and electrolytes, the sweat
glands serve as excretory organ for heavy metals, organic compounds, and
macromolecules. The sweat is composed of 99% water, electrolytes, lactate
(provides an acidic pH to resist infection), urea, ammonia, proteolytic enzymes,
and other substances.
There is a hypothalamic preoptic
sweat center that plays an essential role in regulation of body temperature.
Sweat secretion on palms and soles is more or less continuous (perpetual
sweating) when humans are awake. In contrast, those glands on the general skin
surface respond predominantly to thermal stimuli (thermal sweating). Both types
of sweating can be inhibited by atropine as all sweat glands in different areas
of the body are stimulated by the same sympathetic cholinergic mechanism.
Sweating induced by emotional stress (emotional sweating) can occur over the
whole skin surface, but usually it is confined to palms, soles, axillae, and the
forehead.
The term apocrine glands was given to sweat glands
present in the axillae and anogenital area which are under the control of sex
hormones, mainly androgens. But nowadays by electron microscopy, these apocrine
glands (apocrine = apical part of the cell is destroyed during the process of
secretion) proved to be merocrine in nature (merocrine = no destruction of the
cell during the process of secretion). The "apocrine" sweat of humans has been
described as milky (because it is mixed with sebum due to shared duct) and
viscid, without odour when it is first secreted. Subsequent bacterial action is
necessary for odour production. Unlike eccrine glands which have a duct that
opens onto the skin surface independently of a hair follicle (atrichial),
apocrine glands have a duct that opens into a hair follicle (epitrichial).
Ultrastructure of the Dermo-Epidermal Junction
The most superficial component of the junction is the basal plasma membrane
of keratinocytes, melanocytes and Merkel cells.
Hemidesmosomes superficially resemble focal thickening of the basal
plasma membrane of keratinocytes. At higher magnification, however, they can be
seen to have a complicated ultrastructure which resembles half a desmosome.
Hemidesmosomes consist of an intracellular component, the attachment plaque,
which is associated with tonofilaments, and an extracellular component, known as
the sub-basal dense plate. This latter structure is located in the lamina lucida
(see below) and resembles a fine, dense line parallel to and just beneath the
plasma membrane. Hemidesmosomes are important in maintaining adhesion between
dermis and epidermis.
Immediately beneath the basal plasma
membrane is the basement membrane which consists of three layers: the lamina
lucida, the lamina densa and the lamina fibroreticularis (sub-lamina densa).
Distributed throughout the lamina lucida are anchoring filaments.
Anchoring filaments are very fine structures that are oriented vertically
between the lamina densa and basal plasma membrane.
The lamina densa is an electron dense amorphous layer that lies
parallel to and below the lamina lucida.
Anchoring fibrils are the major constituent of the fibroreticular
layer of the basement membrane. These are short, often curved structures, with
an irregular cross-banding, that insert into the lamina densa and extend into
the upper part of the dermis. They may also insert into amorphous bodies in the
superficial dermis known as anchoring plaques, or curve back to have a second
insertion in the lamina densa.
Another component of the lamina fibroreticularis are the elastic
microfibril bundles, each consisting of many microfibrils that extend into the
dermis and may enmesh with the microfibrillar system of dermal elastic fibers.
Bullous pemphigoid antigen is a glycoprotein synthesized by
keratinocytes and recognized by circulating autoantibodies in patients with
bullous pemphigoid; it has been localized to hemidesmosomes--mainly
intracellularly, but to a lesser degree, also just outside the cells.
Laminin, a high-molecular-weight glycoprotein required for cell
adhesion, has been immunolocalized to lamina lucida. Fibronectin has also been
immunolocalized to the lamina lucida..
Type IV collagen and KF-1 antigen have been immunolocalized to the
lamina densa.
Type VII collagen and Epidermolysis bullosa acquisita
(EBA) antigen have been immunolocalized to anchoring fibrils and plaques. Type
VII collagen has a role in normal dermo-epidermal adherence. AF1 and AF2
antigens have also been immunolocalized to the anchoring fibrils.
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Figure 1: Diagram of the ultrastructure of the dermo-epidermal junction showing the sites of cleavage (blister formation) in the three main types of epidermolysis bullosa, a genetically-determined bullous disorder. |
EB, Epidermolysis Bullosa; AD, Autosomal
Dominant; AR, Autosomal Recessive; DEJ, Dermo-Epidermal Junction; BP Ag, Bullous
Pemphigoid Antigen; LL, Lamina Lucida; LD, Lamina Densa; KF-1, an antigen that
has been immunolocalized to the lamina densa; SLD, Sub-Lamina Densa. ((c) 1994
Dr. Maged N. Kamel)
Champion RH, Burton JL and Ebling FJG (eds): Textbook of Dermatology (Rook),
5th ed, 4 vol, Blackwell, Oxford, 1992
Fitzpatrick TB, Eisen AZ,
Wolff K, Freedberg IM and Austen KF (eds): Dermatology in General Medicine, 3d
ed, 2 vol, McGraw-Hill, New York, 1987
Ganong WF: Review of
Medical Physiology, 14th ed, Appleton & Lange, Connecticut, 1989
Graham-Brown R and Burns T: Lecture Notes on Dermatology, 6th ed,
Blackwell, Oxford, 1990
